Loss of vision in glaucoma is presumed to be due to compression of the optic nerve (ON) head by increased intraocular pressure (IOP), followed by ON degeneration and retrograde death of retinal ganglion cells (RGCs). A better understanding of the mechanisms underlying the RGC and ON degeneration is a prerequisite for developing novel neuroprotective treatments which is currently not available in clinics. Recently endoplasmic reticulum (ER) stress has been shown to play a critical role in neuronal degeneration. Striking RGC-protection has been accomplished by manipulating two key downstream molecules of ER stress, deleting CCAAT/enhancer binding protein homologous protein (CHOP) or activating X-box binding protein 1 (XBP-1). Of special interest, blocking the negative effects of ER stress also inhibited RGC death in a mouse glaucoma model. Thus targeting ER stress may have considerable therapeutic neuroprotective potential in glaucoma. This application will determine whether manipulating ER stress signaling molecules also rescue injured RGC axons in addition to RGC soma protection, through morphology and functional studies. Furthermore, efforts will be made to develop adeno-associated virus (AAV)-mediated gene therapies targeting ER stress to prevent neurodegeneration in mouse glaucoma models. New insights into the critical molecules that regulate RGC soma and axon survival can be translated into novel therapeutic approaches to prevent vision loss in patients with glaucoma.